1. Field of the Invention
The present invention relates to a piperidine derivative and salts thereof, which have excellent antihistaminic activity and antileukotriene activity and are useful as a medicine for broad range of allergic diseases.
2. Background Art
Histamine, which contracts bronchial smooth muscle and promotes capillary permeability when coupled to an H.sub.1 receptor prevailing on the cell membrane, is a significant mediator in allergic diseases. More specifically, histamine is considered to trigger the aggravation of various symptoms of asthma due to its bronchial contractire action, and also to increase the leakage of blood components into intercellular space due to its increasing effect on vascular permeability, to thereby participate in the onset mechanism of allergic rhinitis and the formation of edema in conjunctivitis, etc. In the treatment of allergic diseases as mentioned above, antihistaminic agents have been used. However, conventional antihistaminic agents involve the fear of causing adverse side effects to central nervous system, such as drowsiness, when the agent is coupled to an H.sub.1 receptor in the brain. In recent years, bronchial asthma is considered a chronic airway inflammation until the infiltration of eosinocytes participate. In this connection, attention has been drawn to a late asthma response which manifests airway constriction unique to asthma as a result of infiltration of inflammation cells into bronchial mucosa and hypersecretion from the mucosa.
In the meantime, leukotrienes (LTs) participate in most inflammatory diseases including asthma, psoriasis, rheumatism, and inflammatory colitis, and thus play an important role in inflammation caused by cytotoxic reactions.
Thus, on the basis of the finding that leukotrienes are predominant mediators in allergic reactions and inflammations, there have been discovered a number of substances that suppress the action or the synthesis of leukotrienes in an attempt to relieve these pathological conditions (S. T. Holgate et al.: J. Allergy Clin. Immunol. 98, 1-13 (1996)).
Leukotrienes are arachidonic acid metabolites synthesized by 5-lipoxygenase (5-LO) and are divided into two groups. One group refers to LTB.sub.4 and exhibits strong chemotaxis towards leukocytes. The other group collectively encompasses cysteine leukotrienes (CysLTs), including LTC.sub.4, LTD.sub.4, and LTE.sub.4 ; these substances have long been called "slow-reacting substances of anaphylaxis (SRS-A)." In human tissues, CysLTs exert actions when they are coupled with their receptors. It has been found that a selective LTD.sub.4 receptor inhibitor suppresses the contraction action of both LTC.sub.4 and LTD.sub.4 in human lung tissue, suggesting that the binding site of an LTD.sub.4 receptor f or LTD.sub.4 also serves as a binding site for LTC.sub.4 (Buckner C. K. et al.: Ann. NY Acad. Sci. 1988, 524; 181-186, Aharony D. et al.: New Trends in Lipid Mediators Research, Basel: Karger 1989; 67-71). LTE.sub.4 is also considered to exert its action by the mediation of the same receptor available for LTD.sub.4. But since its activity is low, LTE.sub.4 is considered to be a partially active substance.
Briefly, in allergic diseases such as asthma, pathological profiles of immediate asthma response--i.e., bronchoconstriction and formation of edema in which histamine and similar mediators participate--and those of late asthma response--i.e., airway constriction as a result of cellular infiltration, mucous secretion, hyperplasia of membrane, etc. in which leukotrienes participate--are deemed to play a significant role in the manifestation of pathological conditions. Similarly, the pathological profile of allergic rhinitis also comes to be elucidated as a two-phase reaction including an immediate asthma response phase manifesting ptarmus and hypersecretion of pituita and a late asthma response phase manifesting nasal congestion due to swollen nasal membrane; wherein histamine participates in the former and leukotriene participates in the latter.
Accordingly, it is considered that a compound which exhibits antagonism against both a histamine H.sub.1 receptor and an LTD.sub.4 receptor and which minimally migrates into the brain can serve as a medicine having reduced side effects and is effective for the prevention and treatment of a variety of symptoms from the immediate asthma response phase to the delayed response phase of a broad range of allergic diseases, in particular asthma and rhinitis.
However, until realization of the present invention, a compound exhibiting sufficient antagonism against both the histamine H.sub.1 receptor--which relates to the immediate asthma response phase--and the LTD.sub.4 receptor--which relates to the late asthma response phase--had not yet been found. Moreover, many LTD.sub.4 antagonists which are now being developed have at least one acid group in the molecule and are hydrophilic compounds having high polarity, and inevitably they are not sufficiently absorbed by oral route, leading to an increase in dose of these types of drugs and causing side effects.